Project Summary ? Project 2 It is not known how dopamine depletion in the basal ganglia in Parkinson's disease and the resultant abnormal activity in these structures, alter information processing in brain areas that are downstream from them, specifi- cally the basal ganglia receiving motor thalamus (BGMT). Information processing in the BGMT remains enig- matic. Unlike other areas of the thalamus, the BGMT receives no peripheral glutamatergic input and only weak glutamatergic `driver' input from the cerebral cortex. In addition, it is unique among thalamic nuclei because it is subject to massive inhibitory modulation from the basal ganglia. The BGMT projects to the primary motor cor- tex (M1), the supplementary motor area (SMA) and other cortical areas, but it is not known how these projec- tions influence cortical activities. As we and others have shown, information processing in thalamus and cortex are strongly altered by abnormal basal ganglia output in the parkinsonian state. There is also strong new evi- dence for synaptic (functional/morphologic) plasticity in the parkinsonian state that will further affect the activity of thalamic and cortical neurons (project 3). In the planned studies, we will assess how parkinsonism affects the processing of basal ganglia or cortical inputs to BGMT, and BGMT inputs to motor cortices. Under aim 1, we will use a combination of optogenetic and electrical stimulation methods to probe the impact of activating M1, SMA, or basal ganglia inputs on BGMT activity in normal and parkinsonian (MPTP-treated) monkeys. Based on preliminary findings, we expect to find that light activation of opsin-transfected corticothalamic termi- nals will lead to short-latency excitatory and long-latency inhibitory responses in BGMT, while (electrical) acti- vation of pallidothalamic fibers inhibits BGMT. We will also study interactions between these inputs. In aim 2, we will examine responses of cortical neurons to optogenetic activation of BGMT projections in normal and parkinsonian primates. We expect that the prominent and layer-specific parkinsonism-related plasticity at thalamocortical synapses (project 3) alters responses of cortical neurons to their BGMT inputs. We will particu- larly focus on cortical neurons with antidromic responses to electrical internal capsule stimulation, because the activity of these cells is known to be strongly altered in parkinsonian monkeys. Interactions with project 1 will provide important mechanistic information regarding parkinsonism-related changes in the excitability and spike patterning of thalamic and cortical neurons, while collaboration with project 3 will help us to incorporate mor- phological changes into our analysis. Core B will add essential anatomical results to our study, and will help us by generating parkinsonian animals. Taken together, the planned studies will help us to understand how pal- lidal and cortical inputs shape BGMT activity, how these effects influence M1/SMA activities, and how cortico- thalamic and thalamocortical transmission changes in parkinsonism. This knowledge may alter our view of the pathophysiology of parkinsonism, and will be essential for the rational development or optimization of surgical or pharmacological antiparkinsonian neuromodulation strategies that target basal ganglia or thalamus.